Liver ischemia and reperfusion injury: new insights into mechanisms of innate-adaptive immune-mediated tissue inflammation

Abstract

Ischemia and reperfusion injury (IRI) is a dynamic process that involves two distinctive yet interrelated phases of ischemic organ damage and inflammation-mediated reperfusion injury. Although multiple cellular and molecular pathways contribute and regulate tissue/organ damage, integration of different players into a unified mechanism is warranted. The crosstalk between innate and adaptive immune systems plays a significant role in the pathogenesis of liver IRI. In this review, we focus on recent progress in the mechanism of liver innate immune activation by IR. Kupffer cells (KC), DCs, NK, as well as T cells initiate local inflammation response, the hallmark of IRI, by utilizing distinctive immune receptors to recognize and/or trigger various molecules, both endogenous and exogenous. The interlocked molecular signaling pathways in the context of multiple liver cell types, the IRI kinetics and positive versus negative regulatory loops in the innate immune activation process are discussed. Better appreciation of molecular interactions that mediate these intricate cascades, should allow for the development of novel therapeutic approached against IRI in liver transplant recipients.

Figure 1. Distinctive stages of liver IRI

The ischemic injury, a localized process of hepatic metabolic disturbances, results from glycogen consumption, lack of oxygen supply, and ATP depletion. In the reperfusion injury, an immune activation-mediated amplification process, DAMPs (alarmins) produced during the initial cellular insult, trigger liver non-parenchymal cells (NPC) to generate the pro-inflammatory milieu, which damage the liver tissue directly or indirectly by activating neutrophils and recruiting immune cells from the circulation.

Figure 2. An integrated mechanistic scheme of liver immune activation against IRI

In the first phase of liver IRI, the ischemia insult induces necrotic cell death, which in turn provide diverse “danger” molecules, such as HMGB1 and DNA fragments to activate innate TLR4, RAGE and TLR9 signaling on KCs/DCs and neutrophils. T cells, particularly CD4 Th1 effectors, may also facilitate local innate immune activation via CD154-CD40 pathway. In the second phase of liver IRI, IFN-γ produced by T cells, NKT and NK cells enhances innate immune activation. In addition, CD1d and CD39 activate NKT and NK cells, respectively. The activation progresses via positive and negative regulatory loops. The pro-inflammatory milieu, composed of TNF-α, IL-1β, IL-6, IL-12, CXCL10, CCL2, CXCL8 and ROS, further activates local and recruits circulating immune cells, which promote cytotoxicity against liver parenchymal cells. Meanwhile, IL-10 counter-regulates the sustained pro-inflammatory activation, whereas adenosine receptor 2A inhibits NKT cell activation. Type II NKT cells may also down-regulate IFN-γ production by pro-inflammatory type I NKT cells.